Laser thermal conjunctivoplasty

ABSTRACT

Disclosed is a handheld laser probe for laser thermal conjunctivoplasty, the handheld laser comprising: a forceps; and a line focused laser light source coupled to the forceps, wherein the forceps are configured to grasp a conjunctival fold and hold the fold in a light beam of the line focused laser, and wherein the line focused laser beam is configured to uniformly heat the conjunctival fold held in the forceps. Disclosed are systems for laser thermal conjunctivoplasty including the handheld laser. Disclosed are methods of conjunctivoplasty using the handheld laser probe.

CROSS-REFERENCE

This application is a continuation application of U.S. application Ser.No. 16/487,629, filed Aug. 21, 2019, which is a national phase entryunder 35 U.S.C. § 371 of International Application No.PCT/US2018/019886, filed Feb. 27, 2018, which claims priority benefit ofthe earlier filing date of U.S. Provisional Application No. 62/464,288,filed Feb. 27, 2017, the entire disclosures of each of theseapplications are hereby incorporated by reference in their entiretiesand for all purposes.

STATEMENT OF GOVERNMENT INTEREST

This invention was made with government support under 5 UL1 TR00012810awarded by the NIH National Center for Advancing Translational Sciences.The government has certain rights in the invention.

TECHNICAL FIELD

Embodiments herein relate to the field of eye surgery, and, morespecifically, to a device for, and methods of, performing laser eyesurgery.

BACKGROUND

The white part of the eye (sclera) is covered by a clear membrane calledthe conjunctiva. Like skin, the conjunctiva becomes loose and wrinklywith age. This degenerative condition is called conjunctivochalasis. Theloose folds of conjunctiva often disrupt the uniform distribution oftears and can cause constant eye irritation and blurred vision. Insevere cases, the conjunctival folds protrude onto the inferior eye lidmargin and are traumatized by the lid during blinking. Furthermore, thelid skin is also irritated and altered by the displaced tear.

Conjunctivochalasis is a common cause of tear dysfunction (also referredto as “dry eye”); however, it does not respond to the usual dry eyetreatments such as artificial tears, punctal plugs and anti-inflammatorydrops. Effective treatment requires surgical reduction or excision ofthe redundant conjunctival tissue to reestablish the inferior tearmeniscus and normal tear dynamics. Conjunctivochalasis is typicallydiagnosed by evaluating the conjunctiva for redundant folds thatprolapse onto the lower eyelid and obliterate the tear meniscus in thatregion (see FIGS. 1A to 1C). Cross-sectional optical coherencetomography (OCT) is typically used to evaluate the severity of thecondition and the effectiveness of surgery to remove the redundanttissue.

Surgical means used to remove redundant conjunctival tissue is aneffective way to treat conjunctivochalasis. However, the currentsurgical techniques, such as thermocautery or electrocautery, are notperformed on a widespread basis due to the long painful healing period.Thermocautery is performed with a battery powered hot wire; whileelectrocautery is performed using a radiofrequency diathermy probe Bothtechniques reach very high temperatures exceeding the point of waterboiling and burn the conjunctival epithelium and underlying stroma.Additionally, the burn often extends to the surrounding tissue. Thiscreates a full thickness burn wound that is generally painful, takes upto one month to fully heal and occasionally induces excessiveinflammation and scarring. Furthermore, a chronic inflammatoryconjunctival mass called pyogenic granuloma could result, which wouldnecessitate long-term anti-inflammatory eye drops and possibly furthersurgery. Poor cosmetic appearance (red blots due to bleeding in surfacetissue) during the long healing period also deters patients. Surgicalconjunctival excision with the addition of an amniotic membranetransplant (attached by fibrin glue or suture) can improve the healingcourse, but must be performed in the operating room, which markedlyincreases cost. Thus, the need exist for new and improved surgicaltechniques to treat conjunctivochalasis and other disorders.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments will be readily understood by the following detaileddescription in conjunction with the accompanying drawings and theappended claims. Embodiments are illustrated by way of example and notby way of limitation in the figures of the accompanying drawings.

FIGS. 1A-1C are digital images showing: (A) a photograph ofconjunctivochalasis, with the an arrow pointing to redundantconjunctiva; (B) an image of fluorescein stained conjunctivochalasis,with an arrow showing lid parallel folds; and (C) an optical coherencetomography image of conjunctivochalasis, with an arrow showingobliteration of the tear meniscus.

FIG. 2 is a graph of the absorption coefficient of infrared light forwater and tissue (assuming 80% water content). A desirable absorptioncoefficient of 0.9 to 3 mm⁻¹ (light band) is available using diodelasers or solid state lasers.

FIG. 3A shows a schematic of a laser thermal conjunctivoplasty system,in accordance with embodiments herein.

FIG. 3B shows a schematic of a laser thermal conjunctivoplasty system,in accordance with another embodiment herein.

FIGS. 4A-4F are a set of schematics showing: (A) the application of alaser beam on a fold of redundant conjunctival tissue grasped by forcepsof a handheld laser conjunctivoplasty probe; in accordance withembodiments herein; (B) light focusing optics of a handheld laser probe;in accordance with embodiments herein; (C) light focusing optics of ahandheld laser probe; in accordance with embodiments herein; (D) the raytrace simulation of the embodiment in FIG. 4C. A handheld laser probereceiving laser light through a multimode optical fiber, the output ofwhich is focused by a cylindrical lens into a line; (E), a handheldconjunctivoplasty probe; in accordance with embodiments herein; and (F)a digital image of the handheld conjunctivoplasty probe; in accordancewith embodiments herein.

FIG. 5 is a graph of a laser pulse time profile.

FIG. 6 is a graph of a simulated temperature profile inside theconjunctiva.

FIGS. 7A-7C are a set of schematics showing: (A) a setup for measuringlaser-induced temperature variation using a thermal camera; (B) a setupfor recording the dynamic shrinkage process by a 1310-nm opticalcoherence tomography system; and (C) a procedure to measure theshrinkage from the LTC.

FIG. 8A is a graph of the temperature changes recorded in tissue duringa 1.51 W peak power LTC experiment at three different duty cyclesettings.

FIG. 8B is a graph of the temperature changes recorded in tissue duringa 3.01 W peak power LTC experiment at three different duty cyclesettings.

FIGS. 9A-9B are a set of OCT B-frames showing: (A) the tissueconfiguration before LCT with a rectangular box delineating the regionof interest for particle image velocimetry analysis; and (B) the tissueconfiguration after LTC with a rectangular box delineating the region ofinterest for particle image velocimetry analysis.

FIG. 9C is an image showing particle image velocimetry results obtainedfrom analysis of the regions bounded by the rectangular boxes in FIGS.9A and 9B.

FIG. 10 is a panel of photomicrographs of the treated regions of theporcine eyes before and after LTC with different laser peak powervalues. The duty cycle is set at 20%. The dark regions on the left andright of each photomicrograph are the marks from the tissue marker. Thetop row shows the photographs before LTC and the correspondingphotographs after the LTC are shown in the bottom row.

FIG. 11 is a panel of photomicrographs of the treated regions of theporcine eyes before and after LTC with different pulse duty cycle valuesand a peak power of 3 W. The top row shows the photographs before LTCand the corresponding photographs after the LTC are shown in the bottomrow.

FIG. 12A is a graph showing shrinkage and temperature as a function oflaser peak power. The pulse laser duty cycle is set at 20%. Theshrinkage rate saturates with the increase of the peak power and thetemperature continues to increase with the increase of the peak power.

FIG. 12B is a graph showing shrinkage and temperature as a function ofpulse duty cycle. The laser peak power was set at 3 W. The shrinkagerate saturates with the increase of the duty cycle and the temperaturecontinues to increase with the increase of the duty cycle.

FIG. 13 is a panel of photomicrographs showing tissue shrinkage resultsusing only the forceps or both the forceps and the laser.

FIG. 14 is a graphic outline of an in vivo animal study for laserthermal conjunctivoplasty.

FIG. 15A is a schematic of a 1460-nm LTC system, in accordance with anembodiment herein.

FIG. 15B is a photograph of a prototype LTC system, in accordance withan embodiment herein.

FIGS. 16A-16D is a set of graphs for a prototype 1460-nm diode lasersystem showing: (A) the proportionality between output power and thedriving current; (B) the laser output spectrum at different outputpowers; (C) the temporal characteristics of the output pulse intensityfor different pulse widths; and (D) the output pulse trains withdifferent pulse numbers.

DETAILED DESCRIPTION OF DISCLOSED EMBODIMENTS

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof, and in which are shownby way of illustration embodiments that may be practiced. It is to beunderstood that other embodiments may be utilized and structural orlogical changes may be made without departing from the scope.

Therefore, the following detailed description is not to be taken in alimiting sense, and the scope of embodiments is defined by the appendedclaims and their equivalents.

Various operations may be described as multiple discrete operations inturn, in a manner that may be helpful in understanding embodiments;however, the order of description should not be construed to imply thatthese operations are order dependent.

The description may use perspective-based descriptions such as up/down,back/front, and top/bottom. Such descriptions are merely used tofacilitate the discussion and are not intended to restrict theapplication of disclosed embodiments.

The terms “coupled” and “connected,” along with their derivatives, maybe used. It should be understood that these terms are not intended assynonyms for each other. Rather, in particular embodiments, “connected”may be used to indicate that two or more elements are in direct physicalcontact with each other. “Coupled” may mean that two or more elementsare in direct physical contact. However, “coupled” may also mean thattwo or more elements are not in direct contact with each other, but yetstill cooperate or interact with each other.

For the purposes of the description, a phrase in the form “A/B” or inthe form “A and/or B” means (A), (B), or (A and B). For the purposes ofthe description, a phrase in the form “at least one of A, B, and C”means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B and C).For the purposes of the description, a phrase in the form “(A)B” means(B) or (AB) that is, A is an optional element.

The description may use the terms “embodiment” or “embodiments,” whichmay each refer to one or more of the same or different embodiments.Furthermore, the terms “comprising,” “including,” “having,” and thelike, as used with respect to embodiments, are synonymous, and aregenerally intended as “open” terms (e.g., the term “including” should beinterpreted as “including but not limited to,” the term “having” shouldbe interpreted as “having at least,” the term “includes” should beinterpreted as “includes but is not limited to,” etc.).

With respect to the use of any plural and/or singular terms herein,those having skill in the art can translate from the plural to thesingular and/or from the singular to the plural as is appropriate to thecontext and/or application. The various singular/plural permutations maybe expressly set forth herein for the sake of clarity.

Disclosed herein are a laser thermal conjunctivoplasty (LTC) device,system, and method that provides a safe, fast procedure to treatconjunctivochalasis, for example, in an ophthalmologist's office, byheating and shrinking large volumes of conjunctiva with minimizedcollateral damage and scarring.

Aspects of the present disclosure relate to a handheld laser probe forlaser thermal conjunctivoplasty. In embodiments, the handheld laserprobe includes forceps, such as angled forceps, and a line focused laserlight source, such as a pulsed laser source coupled to the forceps, forexample, mechanically coupled. By line focused laser light, it is meantthat a lens or other device focuses the light to form a line. In otherwords, the light in the focal plane would have the appearance of a line.In embodiments, the forceps are configured to grasp a conjunctival foldand hold the fold in the light beam of the line focused laser while theline focused laser beam is configured to uniformly heat the fold,thereby shrinking large volumes of conjunctiva. In embodiments, thehandheld laser probe device is designed to heat the conjunctival stromaas uniformly as possible to a temperature high enough for collagenshrinkage, but not so high as to cause boiling, mechanical disruption,blood vessel rupture, or bleeding. In embodiments, the laser beamfocuses to a 10 mm line parallel to and just above the angled platformof the forceps (See e.g. FIG. 4C). In embodiments, the handheld laserprobe includes a cylindrical lens to focus the laser light into a line.In embodiments, the handheld laser probe includes a pair of angledforceps, for example angled forceps can be used to grasp a conjunctivalfold while the line focused laser beam is configured to uniformly heatthe fold, thereby shrinking large volumes of conjunctiva. In someembodiments, the angled forceps have tips, forming grasping platformsthat are angled about 30° to about 90° relative to the long axis of thebody of the forceps, for example about, 30° to about 60° or even aboutrelative to the long axis of the body of the forceps. In someembodiments, the grasping platforms have a length that is about the samelength as the line focused laserbeam, for example having a length ofabout to about 15 mm, such as about 10 mm, such as measured from thebend to the tip of the grasping platform. In embodiments, the handheldlaser probe includes a line focused laser light source selected with alaser wavelength, power, pulse duration, and beam focus width to heatwater in conjunctival tissue to shrink its full thickness. Inembodiments, the handheld laser probe includes a line focused laser beamthat has a focal plane with length of about 10 mm and a width of about 1mm.

Because nearly 80% of conjunctiva tissue is water, in embodiments, alaser wavelength is selected at which water is the dominant absorber intissue. In addition, in embodiments, a laser wavelength is selected sothe absorption length is matched to the thickness of conjunctivaltissue. The thickness of the human conjunctiva is approximately 0.24 mm,and loose conjunctiva folded over when grasped by the surgical forcepsshould be approximately 0.5 mm thick. Thus, in embodiments, a wavelengthis selected to heat conjunctival tissue to approximately 0.5 mm depth,i.e. the approximate thickness of the conjunctiva folded over. Inaddition, the energy, power, duration, and/or duty cycle of the laserpulse is chosen so that conjunctival tissue temperature is raised to thepoint of collagen shrinkage but not high enough to cause cellular orvascular rupture. This is much gentler and more controlled than standardsurgical electrocautery, which is heated to the point of tissuevaporization when used to cut conjunctiva. Thus, the disclosed device,system and method provide for a drastic improvement over the techniquescurrently used in the art.

Generally, infrared light absorption in water is higher for longerwavelengths. The desirable absorption wavelengths for water can be foundin the near infrared wavelength band, for example a wavelength fromabout 1.3 μm to about 2.4 μm. Thus, in embodiments a laser light sourceis selected that has a wavelength has a water absorption coefficient of0.1 cm⁻¹ to 100 cm⁻¹, for example, from about 1.3 μm to about 2.4 μm,such as any value in between about 1.3 μm and about 2.4 μm.

From the water absorption spectrum (see FIG. 2 ), it can be seen thatthere are two wavelength bands in tissue that correspond to thewavelength available from commercially available diode lasers. Diodelasers are preferable to other laser sources because of theircompactness, low cost, and reliability. For example, from FIG. 2 , itcan be determined that there is one good diode laser choice at 1.45 μm,and another at 1.9 μm. The 1.45 μm laser diode has higher performanceand lower cost due to its wide use for telecommunications. Thus, inembodiments, a diode laser with a wavelength of about 1.45 μm is usedfor the disclosed device, system, and method. It should be noted,however, that other lasers, such as the 1.9 μm diode laser, a Ho:YAGlaser, and a Cr:Tm:Ho:YAG laser are suitable for use in the discloseddevices, systems, and method. Furthermore, while the lasers discussedabove may be optimal for the disclosed devices, systems, and methods,other lasers could be used as well.

As disclosed, the handheld laser probe includes a pair of forceps tograsp a conjunctival fold and a line focused laser beam to uniformlyheat the fold. The laser energy is typically applied in pulses thatconfine the peak heating to the conjunctival fold. In embodiments, thelaser light source of the handheld laser probe is a pulse laser. Sincethe conjunctiva is approximately 0.24 mm thick as a single layer, thefold held by the forceps would be approximately 0.5 mm. By using a beamfocused into a line with a length of between about 5 mm and about 15 mm,such as about 10 mm, and a width of between about 0.5 mm and about 2 mm,such as about 1 mm, the laser can be focused specifically on theconjunctival fold, thereby reducing the chances of non-selectiveheating. By holding or grasping the conjunctival fold with an angledplatform of angled forceps, the line focused laser beam heats the tissuealong the angled platform of the forceps. In addition, the forceps maybe used to lift the conjunctival fold off the sclera and therebyminimize the chance of damaging the underlying sclera, ciliary body,choroid, and retina. In embodiments, multiple pulses of laser light aredelivered to achieve collagen shrinkage, which can be directlyvisualized by the surgeon. The number of pulses that are delivered tothe tissue may be controlled by a foot pedal.

Aspects of the present disclosure are drawn to a system for laserthermal conjunctivoplasty. In embodiments, the system includes ahandheld laser probe configured for laser thermal conjunctivoplasty,such as described herein, a laser coupled to the handheld laser probe;and a control system coupled to the laser. In some embodiments, thehandheld laser probe is coupled to the laser by a multimode opticalfiber. In embodiments, the control system includes a foot pedal. Inembodiments, the control system includes a controlling circuit tocontrol the laser pulse frequency, duty cycle and pulse energy. Inembodiments, the control system includes a modulator for convertingcontinuous-wave (CW) laser light from the portable laser coupled intopulses. In embodiments, the control system includes an opticalswitch/shutter 140 so that the optical switch/shutter, which can becoupled to and/or actuated by a foot pedal, or other trigger. Thisdesign allows the surgeon to accurately control the laser delivery andmake sure the tissue shrinkage is sufficient while avoiding damage toother tissues. In embodiments, triggers, such as finger, hand, foot,toe, etc., can be used to actuate the optical switch/shutter.

FIG. 3A shows a schematic of a system 100 for thermal conjunctivoplasty,in accordance with embodiments herein. In the embodiment shown in FIG.3A, laser light from a continuous-wave (CW) laser 105 passes through acontrol unit 110 and is then focused into a multimode fiber 120, whichis coupled to a handheld probe 150. Modulator 130 in the control unitconverts the continuous-wave (CW) laser light into pulses, therebyproviding pulsed laser light. A foot pedal 135 controls the opening andclosing of an optical switch/shutter 140 so that the opticalswitch/shutter 140 is open for a selected period of time (e.g. 2seconds) to allow the delivery of a fixed number of pulses. The handheldprobe 150 delivers laser energy to the conjunctiva.

In one embodiment as shown in FIG. 3B, the laser light is controlledthrough a circuit which is connected to a foot pedal switch. The footpedal controls the delivery of the laser pulse from the laser source viathe circuit. A multimode fiber is connected to the laser source anddelivers the laser light into the handheld probe. The handheld probesends the laser energy to the conjunctiva.

FIG. 4A shows the configuration for laser delivery to redundantconjunctival tissue. A line-focused laser beam is delivered to theconjunctive fold held by a pair of forceps. The laser energy is appliedin pulses that confine the peak heating to the conjunctival fold. Sincethe conjunctiva is approximately 0.24 mm thick as a single layer, thefold held by the forceps would be approximately 0.5 mm. Multiple pulsesare delivered to achieve collagen shrinkage, which can be directlyvisualized by the surgeon. The number of pulses that are delivered tothe tissue is controlled by the foot pedal (see FIG. 3 ).

FIG. 4B shows the light focusing optics 155 of the handheld probe, inaccordance with embodiments herein. The light 122 from the multimodefiber 120 is collimated by a collimator 160 to collimated light 162 andthen focused by a cylindrical lens 165, for example, to form a linedirected laser beam 167. In embodiments, the focal length of thecollimator is about 5 to about 20 mm, such as about 10 mm. Inembodiments, the numerical aperture of the multimode fiber is form about0.1 to about 1.0, such as about 0.5. In embodiments, the diameter of thecollimated beam after the collimator is from about 5 mm to about 15 mm,such as about 10 mm. In embodiments, the cylindrical lens 165 focusesthe collimated beam into a line with a length of about 10 mm (range 5 to20 mm) and a width of about 1 mm (range 0.5 to 2 mm).

FIG. 4C shows another embodiment of the invention without using thecollimator. The light from the multimode fiber directly goes through acylindrical lens; the light is focused into a line on the conjunctivatissue with a length of about 10 mm (range 5 to 20 mm) and a width ofabout 1 mm (range 0.5 to 2 mm).

FIG. 4D shows the ray trace simulation of the embodiment in FIG. 4C.

FIG. 4E shows additional details of a handheld laser probe 150. In theembodiment shown, the handheld laser probe 150 receives laser light fromthe multimode fiber 120, which is connected to the probe through fiberconnector, such as an SMA fiber connector. The handheld laser probe 150may include a housing 152 and forceps 170. In embodiments, forceps 170are angled at the end proximal to the beam of the laser with long tissuegrasping platforms 175. In embodiments, the housing 152 includes amechanical holder, such as connecting struts 178 to couple to theforceps 170. In the embodiment shown, the housing 152 includes a fiberadapter 153 to couple the multimode fiber 120 to the housing 152. Thehousing 152 also includes a seal ring 157 for fastening a lens in thelens holder 156.

FIG. 4F shows a photograph of the handheld probe held in hand.

Aspects of the current disclosure relate to methods of laser thermalconjunctivoplasty. The disclosed methods include delivering laser lightfrom a handheld laser probe to a conjunctiva fold, such as a handheldlaser probe including a pair of forceps as disclosed herein. One of theunique aspects of the disclosed methods is that they can easily be donein clinic at a slit-lamp biomicroscope or in a minor procedure roomunder an operating microscope.

As disclosed herein, the devices, systems and methods use the heating ofthe water within conjunctival tissue produced by a laser light. To heatwater in the conjunctival tissue to shrink its full thickness, but nodeeper heating than necessary, the laser pulse duration, duty cycle, andpower, can be optimized. While not being bound by theory, a laser beamfocused into a line on the conjunctival tissue can be modeled as aone-dimensional heat diffusion problem for the calculation of tissuethermal relaxation time:

$\begin{matrix}{\tau = \frac{d2}{4D}} & (1)\end{matrix}$

where T is the thermal relaxation time, D is the heat diffusivity, anddis the heat diffusive length of tissue.

The heat diffusivity is approximately 1.3×10⁻⁷ m² s⁻¹. For a conjunctivafold thickness of 0.5 mm, the thermal relaxation time is about 0.48second. Thus, the pulse duration of the laser should be set to beshorter than about 0.48 second to prevent peak temperature fromdiffusing more than 0.5 mm deeper than the depth at which the laserenergy is absorbed.

In embodiments, the methods include grasping the conjunctiva fold withthe forceps and lifting the conjunctival fold off the sclera and therebyminimizing the chance of damaging the underlying sclera, ciliary body,choroid, and retina.

In embodiments, the laser light source is a pulsed laser. FIG. 5 showsthe schematic of an example laser pulse. The low duty cycle allows ampletime for heat dissipation in deeper tissue to minimize collateraldamage.

Assuming that the pulse is short enough for adiabatic heating, theenergy absorbed by the tissue is calculated as:

ψ(z)=ψ₀ e ^(−μ) ^(a) ^(z)  (2)

Where ψ₀ is the laser fluence, μ_(a) is the absorption coefficient ofwater, the dominant absorber at the wavelength used. So the energydensity inside the tissue can be described as:

μ_(a)ψ₀ e ^(−p) ^(a) z  (3)

The temperature increase inside the tissue will be:

ΔT=μ _(a)ψ₀ e ^(−μ) ^(a) ^(z) /γρs  (4)

Where γ is the water content fraction in tissue, ρ is the mass densityof water and s is the heat capacity of water. The water content of theconjunctiva is assumed to be 80%, the mass density of water is 1000 Kgm3and the heat capacity of water is 4350 J Kg⁻¹° K⁻¹. FIG. 6 shows thetheoretical temperature inside the conjunctiva tissue based on a laserpulse duration of 125 ms, a repetition rate of 1.5 Hz and laser power of535 mW. Within a depth of 0.5 mm (thickness of a conjunctival fold), thetemperature varied between 55-80° C. after the heating. This temperaturerange is ideal for shrinking conjunctival collagen.

In embodiments, the laser light is focused into a line with a length of10 mm and a width of 1 mm.

EXAMPLES Example 1 Ex Vivo Experiment to Optimize Laser Parameters

Ex-vivo eyes, for example porcine, bovine, or human eyes, may be used toassess thermal shrinkage of the conjunctiva. For example, differentlaser energies (for example, between 0.1 and 6.0 W), pulse durations(for example, between 100 and 300 milliseconds), and repetition rates(for example, between 0.5 and 3 Hz) may be investigated to characterizeand optimize the performance the disclosed laser thermalconjunctivoplasty (LTC) systems and methods. Optical CoherenceTomography (OCT) images may be used to evaluate the results.Experimental treatment may be characterized by measuring the shrinkageof conjunctival tissue as measured across the width of the laser heatingline and/or by the absence of mechanical disruption of the treatedconjunctiva or underlying tissue. Within such a framework, experimentaltreatment may be judged to be successful if a threshold of shrinkageexpressed as a percentage change in width is achieved, for example, 50%or greater change in width. An example of such an experiment using exvivo porcine eyes is described below.

Ex-vivo porcine eyes were used to assess thermal shrinkage of theconjunctiva, to optimize the laser parameters, and to verify the NIR LTCperformance. A thermal camera (TiS45, Fluke, Everett, WA, USA) was usedto record the temperature change of the region over time during the LTC.OCT was also used to monitor the tissue structural change during theexperiment. FIG. 7A shows the experimental setup for LTC of a porcineeye (bottom part of figure) and a representative thermal camera image(top part of figure). The thermal camera allows the recording of imagesduring LTC such that the temporal changes in temperature can be obtainedwith a resolution of 33 ms. A custom 1310-nm swept-source OCT systemwith an A-line rate of 50 kHz, a transverse resolution of 15 μm, and anaxial resolution of 8.5 μm was used to monitor the LCT process. FIG. 7Bshows a schematic of the OCT aspect of the experiment. The OCT 8-scancovered a range of 5 mm and repeated 8-scans at the same location wererecorded. The OCT frame rate was 50 Hz. The laser-induced shrinkage wasmeasured using the workflow depicted in FIG. 7C. A 3D-printed marker wasused to create two parallel lines, 10 mm in length and separated by 1mm, on the conjunctiva. A photo of the targeted area was taken using adigital microscope (OMAX, Gyeonggi-do, Korea). The marked region wastreated with NIR LTC and a second photo was taken with the microscope.The shrinkage percentage of the region was calculated from the twophotos taken before and after LTC.

FIG. 8A and FIG. 8B show the temporal changes in temperature during theLTC experiment as measured by the thermal camera. The highest valuedtemperatures in each of recorded thermal camera image sequences wereobtained and plotted versus time. As can be seen from FIG. 8A and FIG.8B, the peak temperature increases rapidly during the laser pulseillumination period and then decreases relatively slowly during theperiod when the laser is off. Three different peak laser powers andpulse duty cycles were investigated. Room temperature was held at −20°C. during the duration of the experiments. At a laser peak power of 1.51Wand 10% duty cycle (100 ms pulse duration), the observed temperatureincreases during laser illumination were very small, with thetemperature never exceeding 40° C. (FIG. 8A). When the duty cycle wasincreased to 20% (200 ms pulse duration) and 30% (330 ms pulseduration), the cumulative effect of multiple pulses were clearly seen.Each laser pulse induced a temperature increase during the illuminationperiod and a temperature decrease during the laser-off period. Thistemperature increase-decrease cycle caused a sustained increase insuccessive peak temperatures attained with each successive pulse. For apeak power of 3 W, the maximum temperature for the 30% duty cycleexceeded 100° C. while the maximum temperature for the 10% duty cyclewas approximately 65° C. (FIG. 8B). When the peak power was increased to5.77 W, the maximum temperature exceeded 100° C. for all three dutycycles (temperature data not shown).

Real-time OCT imaging was used to monitor the LTC-induced shrinkageprocess. This dynamic process can be clearly visualized usingtime-sequence images from OCT B-scans. FIG. 9A and FIG. 9B showexemplary OCT images before and after LTC, respectively. To quantify theshrinkage during the LTC, particle image velocimetry (PIV) was employedto analyze tissue deformation as captured by the OCT B-scan images. FIG.9A and FIG. 9B show the region of interest (denoted by a rectangularbox) encompassing image pixels used to calculate PIV maps. The softwareprogram ImageJ was used to perform the PIV calculation. The results ofthe PIV calculation are shown in FIG. 9C. As shown, the direction andspeed of tissue movement are represented by oriented arrows within therectangular region of interest, with the arrows sized smaller to largerto represent lower and higher local speed magnitudes, respectively.Local speed magnitude is further coded by a grayscale gradient asrepresented in the vertical scale bar of FIG. 9C. In the experimentalmapping depicted here, the large arrow groups at the left and right endsof the region of interest are directed centrally towards the location oflaser-induced heating. This mapping indicates that a shrinkage processis taking place to draw surrounding tissue towards the site of targetedlaser heating.

The influence of different laser parameters on the shrinkage was alsoinvestigated. FIG. 10 shows a panel of microscope images of porcine eyesbefore and after LTC treatment at laser peak powers of 2.33 W, 3.1 W,and 3.66 W. The pulse duty cycle in this experiment was set to 20%. Asdemonstrated, the amount of shrinkage increases as the laser peak powerincreases. For the peak power of 2.33 W, the shrinkage is about 21%.When the peak power is increased to 3.01 Wand 3.66 W, the shrinkageincreases to about 36% and about 45%, respectively.

The experiments described above indicate that a 3.01 W peak power and20% duty cycle provides a favorable amount of tissue shrinkage withoutinducing injurious temperature levels (the measured temperature is about88° C. in the tissue for these parameter values). This peak power (3.01W) was employed to further investigate the influence of the pulse dutycycle on tissue shrinkage. FIG. 11 shows a panel of microscope images oftissue shrinkage using a pulse duty cycles of 10%, 20% and 30%. As canbe seen from these images, at a duty cycle of 10%, the tissue shrinkageis minimal (about 8%). When the duty cycle is increased to 30%, thetissue shrinkage is about 45%. However, a 3.01-W peak power and 30% dutycycle combination also damages the surface of the tissue due toexcessive temperature induction (the surface temperature was measured toreach about 116° C. for these parameter values).

Experiments were also conducted to characterize the relationship betweentissue shrinkage and tissue temperature for different laser parameterscombinations (in this case, laser peak power and duty cycle). For eachspecific laser parameter combination, the tissue shrinkage andtemperature was measured 6 to 8 times on different samples and theresults averaged. FIG. 12A shows the tissue shrinkage and temperature asa function of laser peak power using a default duty cycle of 20%. Asshown, tissue temperature increases as the peak power increases whilethe amount of tissue shrinkage saturates at a peak power of 3 Wandhigher. This suggests that a peak power of about 3 W is well-suited toLTC applications, but that higher peak power levels do not conferadditional beneficial shrinkage effect. FIG. 12B shows tissue shrinkageand temperature as a function of pulse duty cycle using a peak power of3 W. As shown, when the duty cycle is set at 30% the tissue temperaturerises well above 110° C. while the amount of tissue shrinkage iscomparable to that obtained using a 20% duty cycle.

Based on these experimental results obtained using an exemplary 1460-nmlaser system and handheld line-focused laser probe (for example, asdescribed in Example 3 below), in an embodiment, an optimized set of LTCsurgery laser parameters comprises a laser signal having 3-W peak power,1-Hz repetition rate, 20% duty cycle and 4-seconds work duration. Theresultant tissue shrinkage obtained using this parameter set in theexperimental setting described herein was about 40%.

Further experiments were performed to determine the extent to whichgrasping the conjunctival tissue between the forceps during treatmentcontributes to tissue shrinkage via mechanically-induced permanentdeformation. In embodiments, the device is designed to work with angledforceps such that the working distance from the cylindrical lens to thetissue platforms is constant, the incident laser angle is normal to thetissue surface, and only the tissue fold held by the forceps is heated.However, because the forceps impart a mechanical force to the tissuewhile holding it, it is possible that a permanent or transientmechanical deformation is induced in said tissue along withthermally-induced deformation (shrinkage) caused by LTC. To quantify thecontribution of the forceps' mechanical force on tissue deformation, atest was performed wherein tissue was held in the forceps but notexposed to laser light cycling. The distance change between the parallelmaker lines was measured as described earlier. As shown in the leftpanels of FIG. 13 , a change of −10% between the marker lines was foundwhen mechanical force alone was applied. After the LTC (combinedmechanical force and tissue heating), the shrinkage as measure by thechange between the marker lines was found to be about 45% (right panelsof FIG. 13 ).

Example 2 In Vivo Animal Wound Healing Experiments

In vivo animal experiments provide preliminary information on theefficacy and safety of the Laser Thermal Conjunctivoplasty (LTC)procedure. LTC using two different energy settings are performed on theinferior bulbar conjunctiva of one eye of rats that are followed for upto one month after the procedure. The rats are evaluated clinically andby OCT on days 0, 1, 14 and 28 after the procedure (see FIG. 14 ). Theamount of conjunctival shrinkage is measured immediately after theprocedure, by measuring the distance between preplaced marks above andbelow the treatment area. OCT images are taken to evaluate the changesin conjunctival thickness and surface smoothness. The clinicalevaluation assesses the degree of conjunctival hyperemia (a measure ofinflammation), hemorrhage (bleeding inside tissue), and blanching (ameasure of ischemia), if they exist. Digital photography is taken of theeyes before and after staining with fluorescein dye, immediately afterthe procedure and every 2 days, up to day 8. The photographs documentthe clinical appearance and fluorescein staining provides measurement ofthe area of epithelial defect. A randomly designated subset of rats issacrificed at days 0, 1, 14, and 28, and the treated eyes are removedand embedded in paraffin for histochemical staining to evaluate effectsof the laser energy on the conjunctiva and underlying tissues. Eyes arealso embedded for preparing frozen sections that are immunostained forepithelial and fibroblast markers to evaluate and compare the woundhealing reaction to the different laser energy levels. These parametersare compared to treatment of the superior bulbar conjunctiva with thestandard hot wire thermal cautery method to burn/shrink conjunctiva.

Example 3 Exemplary 1460-Nm Programmable Laser Diode System for LCT

FIG. 15A shows an exemplary schematic of a programmable pulsed laserdiode system for use in LTC. In this exemplary embodiment, afiber-coupled high-power laser diode module with a maximumcontinuous-wave (CW) power of 12 W (M1F2S22-1470.10-12C-SS5.x, DILAS,Tucson, AZ, USA) is employed as the light source. The light is outputthrough a multimode fiber with a core diameter of 200 μm and a numericalaperture (NA) of 0.22. The other end of the fiber is connected to ahandheld probe. A 650-nm laser diode is integrated into the source laserfor aiming purpose. The power for the aiming light is 200 μW.

Custom built control circuits are used to drive the 1460-nm lasermodule. The pulse duty cycle, repetition rate, output power, and workingduration are tunable through a programmable control software interface.A 650-nm aiming light can be enabled and disabled by the operator fromthe control software. A foot pedal is used as a trigger for the laseroutput. The laser pulse duty cycle, repetition rate, output power, andworking duration (or the number of pulses) are preset by the controlsoftware. Once the laser output is triggered, the 650-nm aiming light isturned off automatically and the 1460-nm laser is delivered to the probeaccording to the preset parameters. However, if the foot pedal isreleased during the procedure, the infrared laser is turned offimmediately. A photograph of an exemplary prototype LTC laser system isshown in FIG. 15B. In the embodiment shown, the laser system isassembled into a case having dimensions of 41×36×15 cm³.

The power, spectral, and temporal characteristics of the prototype1460-nm laser system were measured. The relationship between outputpower and driving current is shown in FIG. 16A, where a linearrelationship was found. The lasing threshold current was 6.8 A. Thepower was measured by a thermal power sensor (S31OC, Thorlabs, Newton,NJ, USA). FIG. 16B shows the laser spectrum with the output power of 1.2W, 4.1 Wand 6.8 W, respectively. The results were measured by an opticalspectrum analyzer (AQ6370C, YOKOGAWA, Tokyo, Japan). The wavelength atthe peak power is about 1456 nm. No obvious spectral shift was observedas the output power was increased. The spectral bandwidth increased from3.1 nm at 1.2 W to 3.9 nm at 6.8 W. Compared with the bandwidth of thewater absorption peak (about 100 nm), the influence of this spectralbroadening on the LTC may be neglected. The temporal features of thislaser system were measured by a photodetector (PDA10CF, Thorlabs,Newton, NJ, USA) and an oscilloscope (MS04104B-L, Tektronix, Beaverton,OR, USA). FIG. 16C demonstrates the temporal shapes of output pulseswith pulse widths of 100 ms, 200 ms, and 300 ms. FIG. 16D shows theoutput pulse trains with the pulse numbers following the Fibonaccisequence, demonstrating that the output pulse number can be preciselycontrolled by the working duration.

Although certain embodiments have been illustrated and described herein,it will be appreciated by those of ordinary skill in the art that a widevariety of alternate and/or equivalent embodiments or implementationscalculated to achieve the same purposes may be substituted for theembodiments shown and described without departing from the scope. Thosewith skill in the art will readily appreciate that embodiments may beimplemented in a very wide variety of ways. This application is intendedto cover any adaptations or variations of the embodiments discussedherein. Therefore, it is manifestly intended that embodiments be limitedonly by the claims and the equivalents thereof.

We claim:
 1. A handheld laser probe for laser thermal conjunctivoplasty,comprising: a pair of forceps; a laser delivery fiber to deliver thelaser light to the probe; and a cylindrical lens to focus a laser beaminto a line, wherein the forceps are configured to grasp a conjunctivalfold and, and the line-focused laser beam is configured to uniformlyheat the conjunctival fold.
 2. The handheld laser probe of claim 1,wherein the forceps have angled long tissue platforms.
 3. The handheldlaser probe of claim 1, wherein the cylindrical lens focuses laser lightinto a line with a length of about 10 mm and a width of about 1 mm.
 4. Asystem for laser thermal conjunctivoplasty, comprising: a handheld laserprobe configured for laser thermal conjunctivoplasty, comprising: a pairof forceps; and a line focused laser beam coupled to the forceps,wherein the forceps are configured to grasp a conjunctival fold, andwherein the line focused laser beam is configured to uniformly heat theconjunctival fold held in the forceps; a laser light source coupled tothe handheld laser probe; and a control system coupled to the laser. 5.The system of claim 4, wherein the line focused laser beam comprises apulse laser beam.
 6. The system of claim 4, wherein the handheld laserprobe is coupled to the laser by a multimode optical fiber.
 7. Thesystem of claim 4, wherein the control system comprises a foot pedal. 8.The system of claim 4, wherein the control system comprises a modulatorfor converting continuous-wave (CW) laser light from the laser lightsource into pulses.
 9. The system of claim 4, wherein the control systemcomprises an optical switch/shutter coupled to a trigger for actuationof the optical switch/shutter.
 10. The system of claim 4, wherein thecontrol system comprises an electrical circuit.
 11. The system of claim4, wherein the laser light source is selected with a laser wavelength,power, pulse duration, and beam focus width to heat water inconjunctival tissue to shrink its full thickness.
 12. The system ofclaim 4, wherein the laser light source has a central wavelength with awater absorption length of 1-100 mm⁻¹.
 13. The system of claim 4,wherein the laser light source has a pulse duration of 5 milliseconds to500 milliseconds.
 14. The system of claim 4, wherein the laser lightsource has a repetition rate of 0.5-20 Hz.
 15. The system of claim 4,wherein the line focused laser beam has a focal plane and the laser beamin the focal plane has a length of about 10 mm and a width of about 1mm.